Dicyclopentyl Dithiosquarate as an Intermediate for the Synthesis of Thiosquaramides

Article abstract of DOI:10.1021/acs.orglett.7b03549

A general and greatly improved route is reported for the synthesis of a variety of thiosquaramides from a common dithionated intermediate. Both diaryl thiosquaramides and bifunctional thiosquaramides are readily accessed from dicyclopentyl dithiosquarate via two addition-elimination reactions. The convenient handling characteristics and relative stability of associated intermediates enable an operationally simple thiosquaramide preparation. Bifunctional aryl thiosquaramides, which were inaccessible by the previous method, are also prepared, and their catalytic performance is demonstrated, including their capability to function as Br?nsted acid catalysts.

Full text of DOI:10.1021/acs.orglett.7b03549

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Dicyclopentyl Dithiosquarate as an Intermediate for the Synthesis of
Thiosquaramides
Michael Rombola and Viresh H. Rawal*
Department of Chemistry, University of Chicago, 5735 South Ellis Avenue, Chicago, Illinois 60637, United States
S
* Supporting Information
ABSTRACT: A general and greatly improved route is
reported for the synthesis of a variety of thiosquaramides
from a common dithionated intermediate. Both diaryl
thiosquaramides and bifunctional thiosquaramides are readily
accessed from dicyclopentyl dithiosquarate via two addition−
elimination reactions. The convenient handling characteristics
and relative stability of associated intermediates enable an
operationally simple thiosquaramide preparation. Bifunctional
aryl thiosquaramides, which were inaccessible by the previous
method, are also prepared, and their catalytic performance is
demonstrated, including their capability to function as
Brønsted acid catalysts.
ince the advent of hydrogen bond donor catalysis,1 two
preparation of even more acidic thiosquaramides, thereby
enabling further advances in catalysis. Of particular interest
were the hitherto unexplored bifunctional aryl thiosquaramides,
which were expected to be among the most acidic members of
the bifunctional squaramide family of catalysts. Among the
challenges that one faces while developing a general route to
these catalysts is the instability of many thiosquarate
intermediates. The size of the alkyl group on the thiosquarate
precursor affects its stability and its reactivity to amines. In prior
studies, for example, we had found that the synthesis of
dimethyl dithiosquarate presented difficulties, and the mono-
displacement intermediates of other squarates were unstable to
reaction conditions and standard purification methods.
Through extensive studies, we have determined that certain
bulkier secondary thioesters possess the needed reactivity and
stability properties to serve as common intermediates to a wide
range of thiosquaramides, including the sought-after bifunc-
tional aryl thiosquaramides (Scheme 1).
2
Sscaffolds have emerged as dominant platforms: thioureas
and squaramides.3,4 The success of these compounds as
catalysts can be attributed to the two-point hydrogen bond
donor motif, which provides strong substrate activation and
spatial orientation for asymmetric induction. The simple and
routine nature of thiourea and squaramide preparations has
contributed to their widespread adoption as catalysts:
Thioureas are prepared in one step from an appropriate
isothiocyanate and amine, and squaramides are prepared in two
steps from dimethyl squarate and two amines (Scheme 1).
Almost any amine can be used as a coupling partner, which
allows the chemist to quickly build a library of compounds for
screening in their reaction of interest.
Scheme 1. General Synthesis of Squaramides and
Thiosquaramides
Several alkyl squarates were prepared and subjected to
different thionation conditions, and illustrative results are
summarized in Table 1. Thionation of n-butyl squarate 1a using
Lawesson’s reagent gave the unstable, gelatinous dithiosquarate
2a. The reaction was stopped at partial conversion, since the
product decomposed as the reaction progressed. Squarates of
secondary alcohols gave better results. On reaction with 1 equiv
of Lawesson’s reagent at room temperature in dichloro-
methane, 3-pentyl squarate 1b was converted to a near 1:1
mixture of the mono- and dithiosquarates (3a and 2b) after 14
h, and completely to the latter after 46 h (entries 2 and 3).
Cyclopentyl squarate 1c was converted to the dithio-derivative
We recently reported the first example of thiosquaramides as
excellent hydrogen bond donors for asymmetric catalysis.5
While our method of catalyst preparation provided access to
bifunctional alkyl thiosquaramides, it proved ineffective for
making bifunctional aryl thiosquaramides, or aryl thiosquar-
amides more generally.6,7 The development of an improved and
general synthesis of thiosquaramides, through a standardized
and user-friendly procedure, was expected to allow the
Received: November 15, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03549
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Thionation of Alkyl Squarates with Lawesson’s
Table 2. Addition of Amines to Cyclopentyl Dithiosquarate
Reagent
Lawesson’s reagent
time
(h)
yield
(%)
entry
R
(equiv)
X
1
2
n-butyl (1a)
1.0
1.0
7
S (2a)
14
3-pentyl (1b)
14
S (2b),
O (3a)
30, 39
3
4
3-pentyl (1b)
1.0
1.0
46
37
S (2b)
S (2c)
80
71
cyclopentyl
(1c)
5
cyclopentyl
0.5
25
O (3b)
68
(1c)
(2c) in good yield; workup of the reaction followed by silica gel
chromatography afforded the pure dithione as a fluffy orange
solid. The use of 0.5 equiv of Lawesson’s reagent gave the
monothionation product (3b) in good yield.
Of the different dithiosquarates examined, dithiosquarate 2c
has been found to be the preferred intermediate for making
thiosquaramides because of its superior handling characteristics
and reactivity, especially with less reactive amines, such as
electron-deficient anilines. Whereas dithiosquarate 2b is a red
oil that continues to darken, 2c is a stable solid: a sample left
under ambient conditions displayed no noticeable decom-
position after 1 week.
Cyclopentyl dithiosquarate (2c) provided an excellent
platform for the synthesis of various di- and monodisplacement
squaramide derivatives (Table 2). Primary and secondary
amines reacted vigorously with 2c. Indeed, if no cooling was
employed or the addition of the amine was too rapid, the
reactions with benzylamine or cyclohexylamine to produce 4a
or 4b were sufficiently exothermic as to cause the solvent to
boil. Sterically bulky amines were less reactive. Addition of tert-
butyl amine produced the desired thiosquaramide 4c in only
30% yield after 2 h. Longer reaction times did not improve
yield (36% yield after 42 h), and using an excess of the amine
led to byproduct formation. Treatment of 2c with an excess of
the appropriate aniline led to diaryl thiosquaramides.8 Even the
electron-deficient 3,5-(bistrifluoromethyl)aniline was a suitable
reaction partner, producing the diaryl thiosquaramide 4f in the
absence of a catalyst.9 The bulkiness of the amine heavily
influenced its rotameric composition. NMR experiments
revealed compound 4c existed as a single rotamer in DMSO
at room temperature, while compound 4a existed as three
rotamers in a ratio of 26:9:2. Compound 4b is present
predominantly as one rotamer.
Despite the high reactivity of 2c toward addition−
elimination reactions, monodisplacement products can still be
prepared by using less than 1 equiv of the amine (entries 7−
12). The slightly lower isolated yield of cyclopentyl
dithiosquarate 5c than 3-pentyl dithiosquarate 5d belies the
greater reactivity of 2c over 2b. The lower yield of 5b is due to
competitive diaryl thiosquaramide formation, indicating that
the monoaddition product is quite reactive to a second
addition−elimination reaction.
a
Compound 2b was used instead of 2c.
enantioselective barbituric acid additions to nitroalkenes.5
Importantly, the present route to 6a is not only more robust,
but, unlike the earlier route, it also opens access to bifunctional
thiosquaramides possessing various anilines. Some bifunctional
thiosquaramides are sensitive to silica gel chromatography.
Catalysts 6b, 6c, and 6e and were isolated by silica gel
chromatography, whereas 6a, 6d, 6f, and 6g were isolated by
trituration. Bifunctional thiosquaramides, especially those
possessing an aryl substituent, display complex NMR spectra,
presumably due to the presence of zwitterionic species and
restricted rotation (Scheme 3). We have found that protonation
of these compounds with HCl simplifies their spectra and
sharpens many signals.
When coupled with a chiral diamine, the monodisplacement
products provide access to various bifunctional thiosquaramide
catalysts (Scheme 2). Thus, monobenzylamino dithiosquarate
5a was converted in 90% yield to 6a, a catalyst that was used for
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DOI: 10.1021/acs.orglett.7b03549
Org. Lett. XXXX, XXX, XXX−XXX

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Scheme 2. Bifunctional Thiosquaramide Synthesis
Scheme 5. Evaluation of Oxo- and Thiosquaramide Catalyst
Performance
a
a
1
Conversion determined by H NMR spectroscopy.
higher than that obtained using our recently reported
bifunctional alkyl thiosquaramide 6a. These initial studies
demonstrate the superior capability of this new class of
bifunctional catalysts.
Furthermore, the higher acidity expected of aryl thiosquar-
amides5,7a opens up the possibility of their functioning as
Brønsted acids.11 To probe this capability, we examined the
aza-Diels−Alder reaction between 2-siloxydiene 13 and N-
benzylideneaniline 14, which has been reported to be catalyzed
by bis(trifluoromethane)sulfonimide (Tf2NH) to afford
tetrahydropyridine 14 in up to 85% yield and 4:1 dr (Scheme
6).12,13 Remarkably, the reaction catalyzed by thiosquaramide
Scheme 3. Protonation of Bifunctional Thiosquaramides for
NMR Characterization
Scheme 6. Aza-Diels−Alder Reaction Using a
a
Thiosquaramide as a Brønsted Acid Catalyst
The described methodology also allows the synthesis of
bifunctional monothiosquaramides with complete regiocontrol
(Scheme 4). The reaction of tert-butylaminomonothiosquarate
7, obtained upon selective displacement of the alkoxy in
conjugation with the thiocarbonyl group, with the requisite
chiral diamine yielded bifunctional monothiosquaramide 8.
Compound 8, like its dithio-congener, is more soluble in
CH2Cl2 than the corresponding dioxosquaramide. Conversion
of even one of the carbonyl groups to a thiocarbonyl disfavors
the formation of hydrogen bonded ladder networks of
oxosquaramides. This new class of squaramides promises to
open up further opportunities in catalysis.
a
1
Yield determined by H NMR spectroscopy using 1,3,5-trimethoxy-
benzene as an internal standard.
Scheme 4. Bifunctional Monothiosquaramide Synthesis
4f afforded DA-adduct 15 in 77% yield with a 2.7:1 dr (major
diastereomer shown). Neither the oxosquaramide of 4f nor
Schreiner’s thiourea catalyzed the reaction, yielding only
recovered starting material.14 We are currently developing
chiral aryl thiosquaramides for the catalysis of asymmetric
reactions.
In summary, we have developed a unified route to
thiosquaramides. Bifunctional aryl thiosquaramides have been
made for the first time, and their catalytic performance has been
demonstrated, as has the potential for their use as Brønsted acid
catalysts. The ready access to this new class of catalysts is
expected to further expand the reaction space in hydrogen
bonding catalysis.
Since bifunctional aryl thiosquaramides have not been
previously reported, we have carried out preliminary studies
to calibrate their performance against their oxosquaramide
counterparts in the known conjugate addition reaction of
lawsone (9) to β,γ-unsaturated α-keto ester 10 (Scheme 5).10
All thiosquaramides tested gave higher enantioselectivities than
their corresponding oxosquaramides. Moreover, even without
any optimization, bifunctional aryl thiosquaramide 6d gave the
conjugate addition product in 94% ee, which is considerably
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(9) The spectroscopic data for 4f are consistent with those of 4d and
4e, but differed from that reported in the literature. Cf. ref 7a.
(10) (a) Chen, X.; Zheng, C.; Zhao, S.; Chai, Z.; Yang, Y.; Zhao, G.;
Cao, W. Adv. Synth. Catal. 2010, 352, 1648. (b) Wang, Y.; Zhang, W.;
Luo, S.; Zhang, G.; Xia, A.; Xu, X.; Xu, D. Eur. J. Org. Chem. 2010,
2010, 4981. (c) Gao, Y.; Ren, Q.; Ang, S.; Wang, J. Org. Biomol. Chem.
2011, 9, 3691. (d) Lee, J. H.; Kim, D. Y. Bull. Korean Chem. Soc. 2013,
34, 1619.
(11) Recent reviews: (a) Akiyama, T.; Mori, K. Chem. Rev. 2015, 115,
9277. (b) Min, C.; Seidel, D. Chem. Soc. Rev. 2017, 46, 5889.
(12) Takasu, K.; Shindoh, N.; Tokuyama, H.; Ihara, M. Tetrahedron
2006, 62, 11900.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03549.
Experimental procedures and detailed characterization
data of all new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: vrawal@uchicago.edu.
ORCID
(13) For examples of Brønsted acid catalyzed enantioselective aza-
Diels−Alder reactions, see: (a) Rueping, M.; Raja, S. Beilstein J. Org.
Chem. 2012, 8, 1819. (b) Beceno, C.; Krappitz, T.; Raabe, G.; Enders,
̃
D. Synthesis 2015, 47, 3813. (c) Hatanaka, Y.; Nantaku, S.; Nishimura,
Y.; Otsuka, T.; Sekikaw, T. Chem. Commun. 2017, 53, 8996.
(d) Review: Heintzelman, G. R.; Meigh, I. R.; Mahajan, Y. R.;
Weinreb, S. M. Diels-Alder Reactions of Imino Dienophiles. In Organic
Reactions; Overmann, L. E., Ed.; Wiley: 2005; Vol. 65, Chapter 2.
(14) Since oxosquaramide (12e) is poorly soluble in PhMe, the
reaction was also performed in CH2Cl2, but gave no product.
Michael Rombola: 0000-0002-4402-5619
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Science Foundation (NSF-1566402) for
financial support of this work.
REFERENCES
■
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D
DOI: 10.1021/acs.orglett.7b03549
Org. Lett. XXXX, XXX, XXX−XXX